miR-181a/b downregulation: a mutation-independent therapeutic approach for inherited retinal diseases

EMBO Mol Med. 2022 Nov 8;14(11):e15941. doi: 10.15252/emmm.202215941. Epub 2022 Oct 4.


Inherited retinal diseases (IRDs) are a group of diseases whose common landmark is progressive photoreceptor loss. The development of gene-specific therapies for IRDs is hampered by their wide genetic heterogeneity. Mitochondrial dysfunction is proving to constitute one of the key pathogenic events in IRDs; hence, approaches that enhance mitochondrial activities have a promising therapeutic potential for these conditions. We previously reported that miR-181a/b downregulation boosts mitochondrial turnover in models of primary retinal mitochondrial diseases. Here, we show that miR-181a/b silencing has a beneficial effect also in IRDs. In particular, the injection in the subretinal space of an adeno-associated viral vector (AAV) that harbors a miR-181a/b inhibitor (sponge) sequence (AAV2/8-GFP-Sponge-miR-181a/b) improves retinal morphology and visual function both in models of autosomal dominant (RHO-P347S) and of autosomal recessive (rd10) retinitis pigmentosa. Moreover, we demonstrate that miR-181a/b downregulation modulates the level of the mitochondrial fission-related protein Drp1 and rescues the mitochondrial fragmentation in RHO-P347S photoreceptors. Overall, these data support the potential use of miR-181a/b downregulation as an innovative mutation-independent therapeutic strategy for IRDs, which can be effective both to delay disease progression and to aid gene-specific therapeutic approaches.

Keywords: inherited retinal diseases; miR-181; mitochondria; photoreceptor; therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Down-Regulation
  • Humans
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Mutation
  • Retina / pathology
  • Retinitis Pigmentosa* / genetics
  • Retinitis Pigmentosa* / metabolism
  • Retinitis Pigmentosa* / therapy


  • MicroRNAs